1. Field of the Invention
This invention relates to aminoquinoline derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to 2-quinolyl(azacycloalkylalkyl)amines and pharmaceutical compositions and preparations containing such compounds. It also relates to the use of such compounds in the treatment or prevention of neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain. The dopamine D4 receptor subtype has recently been identified. See Nature 350: 610 (Van Tol et al., 1991) and Nature, 347: 146 (Sokoloff et al., 1990) Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D4 receptor plays a role in the etiology of schizophrenia Consequently, selective D4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
U.S. Pat. No. 5,093,333 describes N-substituted-2-aminoquinolines said to be M1 receptor agonists.
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. A broad aspect of the invention is directed to compounds of Formula I: 
wherein:
R1, R2, and R3 independently represent hydrogen, halogen, C1 -C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R6 is hydrogen or C1-C6 alkyl; and
Q represents a substituted azacycloalkylalkyl group of the formula: 
where
W is nitrogen, CH or COH;
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms; and
T is an aryl or heteroaryl moiety optionally substituted with up to two groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I.
Since dopamine D4 receptors are concentrated in the limbic system (Taubes, Science 265: 1034, 1994) which controls cognition and emotion, compounds which interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. In addition, disorders involving memory impairment or attention deficit disorders can be treated with the compounds of this invention. These compounds interact specifically with the dopamine D4 receptor subtype.
The compounds of the invention demonstrate high affinity and selectivity in binding to the D4 receptor subtype. The use of the compounds of this invention in methods of treating neuropsychological disorders is predicated on the ability of the compounds to bind selectively to a dopamine receptor subtype, the D4 receptor. The compounds of the invention can therefore be used in the treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 receptors.
Thus, in another aspect, the invention provides methods for treating and/or preventing neuropsychological disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. It also provides methods of treating affective disorders such as Alzheimer""s disease and certain movement disorders such as Parkinsonism and dystonia.
The invention further provides methods for treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
In addition to the compounds of Formula I above, the invention encompasses compounds of Formula IA: 
wherein:
R1, R2, R3, R4 and R5 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R6 is hydrogen or C1-C6 alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
In Formula IA, the dashed segment represents either a single bond resulting in a 3,4 dihydroquinoline; or a double bond resulting in a quinoline.
In the compounds of the invention, xe2x80x9cWxe2x80x9d preferably represents nitrogen or COH. Preferred xe2x80x9cTxe2x80x9d groups in Formula I are 6-membered carbocyclic aromatic ring systems having zero, one or two nitrogen atoms. Particularly preferred xe2x80x9cTxe2x80x9d groups are phenyl, 2-pyridinyl, and 2-pyrimidinyl. The particularly preferred xe2x80x9cTxe2x80x9d groups are optionally mono- or disubstituted with halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
Preferred compounds of Formula IA are those where R6 is hydrogen, methyl or ethyl.
Preferred xe2x80x9cTxe2x80x9d groups in Formula I are 
The invention also provides compounds of Formula II: 
wherein:
R1, R2, R3, R4 and R5 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R6 is hydrogen or C1-C6 alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
Preferred compounds of Formula II are those where R6 is hydrogen, methyl or ethyl. Particularly preferred compounds of Formula II are those where
In addition, the invention encompasses compounds of Formula III: 
wherein:
R1, R2, R3, R4 and R5 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R6 is hydrogen or C1-C6 alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
In preferred compounds of Formula III, R6 is hydrogen, methyl or ethyl.
In certain situations, compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For example, where R6 in Formula I is a methyl group, the resulting compound can be present as (R) and (S) stereoisomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as, for example, acetic, xe2x80x94HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, such as, for example, oxalic (n=0), and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
By the terms (C1-C6)alkyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms as well as cyclic alkyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmethyl.
By the terms (C1-C6)alkoxy and lower alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.
By hydroxy C1-C6 alkyl is meant a C1-C6 alkyl group carrying a terminal hydroxy moiety.
By halogen, halo, or halide is meant fluorine, chlorine, bromine and iodine substituents.
The binding characteristics of compounds of Formula I for the D4 receptor, expressed in nM, generally range from about 0.5 nanomolar (nM) to about 50 nanomolar (nM). These compounds typically have binding constants for the D2 receptor of from at least about 100 nM to more than 3000 nM. Thus, the compounds of the invention are generally at least about 3, preferably at least about 5, and most preferably at least about 10 time more selective for the D4 receptor than the D2 receptor. Even more preferably, these compounds are at least 20, and more preferably at least 25-50, times more selective for the D4 receptor than the D2 receptor.
As noted above, the invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the and partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preparation of 2-Aminoalkylaminoquinolines
The compounds of Formula I, and the pharmaceutically acceptable acid addition salts thereof, may be prepared according to the reactions shown below in Schemes I and II. 
wherein R1-R6, W, Y and Z are as defined above for Formula I.
As shown in Scheme I, a quinoline of general structure IV, possessing an appropriate leaving group (X) at the 2 position, e.g., a halogen or S-methyl group, may be reacted with a primary or secondary amine of general structure V in the presence of a base to afford a compound of Formula I as the desired product. The reaction may be carried out at elevated temperature with or without a solvent. Further, the reaction mixture may also contain an acid scavenger such as diisopropylamine or an inorganic salt such as ammonium chloride.
Where they are not commercially available, the compounds of general structure IV may be prepared by literature procedures or procedures analogous to those described in the literature. Compounds of general structure V are either known or capable of being prepared by the methods known in the art. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.
Alternatively, compounds of the invention may be prepared according to the reactions shown in Scheme II. Thus, compounds may be prepared from readily available substituted or unsubstituted 4-haloquinoline compounds by allowing them to react with a Wittig reagent. such as an alkyl triphenylphosphonate generated from an alkyltriphenylphosphonium halide; plus a base, such as n-butyllithium in an organic solvent, such as tetrahydrofuran. The resulting 4-alkylquinoline can be converted to a 4-alkyl-2-haloquinoline by treatment with an oxidizing agent, such as m-chloroperbenzoic acid (MCPBA) in an appropriate solvent, such as chloroform, to give the corresponding 4-alkylquinoline N-oxide, followed by reaction with a halogenating agent, such as phosphorus oxychloride to give a 4-alkyl-2-haloquinoline of Formula IVa. Reaction of 2-haloquinoline IVa with amines of Formula V as described above, yields compounds of this invention. 
wherein R1-R6 are as defined above, R1 is alkyl of 1 to 4 carbon atoms, and X is halogen.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.